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Females are more susceptible than males to many autoimmune diseases. The processes causing this phenomenon are incompletely understood. Here, we demonstrate that aged female mice acquire a previously uncharacterized population of B cells that we call age-associated B cells (ABCs) and that these cells express integrin ␣ X chain (CD11c). This unexpected population also appears in young lupus-

Hemophagocytic lymphohistiocytosis (HLH) is a rare disorder with familial and acquired forms. The familial form is associated with mutations in the perforin gene and both forms are associated with severe defects in lymphocyte cytotoxic function. We examined perforin-deficient mice as a model of HLH in order to gain insight into this poorly understood disorder. While these mice do not spontaneously develop HLH-like symptoms, we found that they manifest all of the features of HLH after infection with lymphocytic choriomeningitic virus (LCMV). Following LCMV infection, perforin-deficient mice develop fever, splenomegaly, pancytopenia, hypertriglyceridemia, hypofibrinogenemia, and elevation of multiple serum cytokine levels, and hemophagocytosis is evident in many tissues. Investigation into how this phenotype develops has revealed that CD8 ؉ T cells, but not natural killer (NK) cells, are necessary for the development of this disorder. Cytokine neutralization studies have revealed that interferon gamma (IFN␥) is uniquely essential as well. Finally, the excessive amount of IFN␥ seen in affected mice appears to be driven by increased antigen presentation to CD8 ؉ T cells. These studies provide insight into the pathophysiology of HLH, and provide new targets for specific therapeutic intervention in this fatal disorder. IntroductionHemophagocytic lymphohistiocytosis (HLH) is a rare disorder with both familial and acquired forms. [1][2][3] Specific criteria for the diagnosis of this disorder have been established (Table 1). 4 As a familial disorder, it has an autosomal recessive inheritance and usually affects infants. As an acquired disorder, it is more variable and affects a wider age range. Acquired, or secondary, HLH has been associated with infection (most commonly with Epstein-Barr virus [EBV]), malignancy, and autoimmunity. Familial cases also commonly appear to be triggered by viral infection. While some of the features of HLH, including hemophagocytosis, can be seen in circumstances with significant immune activation, the diagnosis of this disorder is limited to situations where all of the diagnostic criteria are met.In addition to the diagnostic features listed in Table 1, patients with HLH variably display a number of other characteristic features, such as hepatomegaly, jaundice, adenopathy, rash, seizures, and focal neurologic deficits. When assayed, patients have been found to have strikingly high serum levels of numerous cytokines including interferon gamma (IFN␥), tumor necrosis factor ␣ (TNF-␣), interleukin 6 (IL-6), IL-10, and macrophagecolony-stimulating factor (M-CSF). [5][6][7][8][9] Histologic examination of lymphoid tissues reveals a mixed infiltrate of lymphocytes and macrophages that appear highly activated. Liver biopsies typically display periportal infiltrates composed of lymphocytes and macrophages. Bone marrow biopsies may variably reveal hypoplasia or aplasia. 1 Overall, patients with HLH appear to have striking activation of the immune system by both clinical and laboratory measures. It i...